Compositions and Methods for Treating and Removing Seborrheic Keratoses

ABSTRACT

A method of diminishing the appearance of or effecting the removal or disappearance of seborrheic keratoses by the application of compositions containing a) one or more, preferably a combination of, dietary antioxidants and/or antioxidant sources, b) one or more hydrating agents and c) one or more keratolytic agents.

RELATED APPLICATIONS

The present application claims the benefit and priority of previouslyfiled U.S. Provisional Application No. 62/455,559 filed Feb. 6, 2017 and62/575,031 filed Oct. 20, 2017, both having the same title and inventoras the instant application, the contents of which are herebyincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to compositions and methods with which totreat and reduce, if not remove, seborrheic keratoses from the skin.Specifically, the application of specific topical compositionscontaining select antioxidants, especially dietary antioxidants, to skinmanifesting seborrheic keratosis has been found to diminish themanifestation of the seborrheic keratosis as well as facilitate, if notcause, the exfoliation of seborrheic keratoses from the skin. Inaddition, the combination these select antioxidants with other skinenhancing/remedial additives, most especially hydrating/humectant agentsand/or keratolytic agents, are found to supplement and/or promote theeffect of the select dietary antioxidants as well as to counteractand/or mask irritation and skin damage that may arise therefrom.

BACKGROUND OF THE INVENTION

Seborrheic keratosis (SK) is a type of non-cancerous growth or tumor ofthe epidermis or outer layer of the skin. There is no single cause forthe manifestation of seborrheic keratosis though heredity, sun exposure,and the like are believed to play some role. Two genes, including FGFR3and PIK3CA, may play a role in SK development. Mutations in these genesalso are associated with SKs (Berman and Zacharias). Seborrheickeratoses typically begin to appear later in life, especially as oneages through their 40s and into their 50s. These tumors, or lesions asthey are oftentimes referred to, are commonly characterized as havingthe appearance of wax or a wax-like substance on the skin and typicallyrange in size from very small to an inch or more in diameter: thoughthey are not necessarily round.

Although there is some indication that seborrheic keratosis may lead orprogress to squamous cell carcinoma, for the most part, these lesionsare benign and harmless. Still, depending upon the location, color,size, etc. of the tumors, they can be unsightly. Additionally, they maybecome itchy or periodically bleed, especially if the tumor or tumorsare in areas prone to the rubbing of fabric and the like. In theseinstances, individuals oftentimes seek to have the tumors removed:again, more as an aesthetic treatment than a medical treatment. Finally,because these tumors can take on the appearance of other skin maladies,including melanoma or squamous cell carcinoma, it is sometimes desirableto remove the tumor to remove the risk and, if truly of concern, to havethe tumor examined to rule out melanoma.

There are several treatments or methods for the removal of seborrheickeratosis including cryosurgery where the tumor is frozen with liquidnitrogen and then allowed to slough off, curettage where specialinstruments are used to scrape off or thinly shave off the tumor;electrodessication where the tumor is burned off with an electriccurrent, and ablation where the tumor is vaporized through differenttypes of laser treatments as well as select combinations of theforegoing. All of these are expensive and are, and in many instancesmust be, administered by a medical professional.

Recently, there has been some movement towards the use of silver,specifically colloidal silver solutions and gels, in the treatment ofseborrheic keratosis; however, the effectiveness is still underinvestigation and, in any event, topical application can and oftentimesdoes lead to skin discoloration in the treated area and oral consumptioncan lead to argyria where the whole of one's skin can turn blue.

More recently, a report has issued asserting that the application ofurea and lactate was, effective in reducing seborrheic keratosis whichare said to melt away after several months.

Despite these continued efforts, there still remains a need for aneffective, easy to apply, fast acting treatment for use in reducing orremoving seborrheic keratoses. Most especially, there is a need formethods and treatments that can be used at home and purchasedover-the-counter and which are free of, or substantially free of,undesirable side effects and which are effective with topicalapplication for six weeks or less, preferably four weeks or less.

SUMMARY OF THE INVENTION

According to the first aspect of the present teaching there are providedtopically applied compositions for the treatment of seborrheic keratosiswhich compositions comprises a) one or more, preferably a combinationof, select antioxidants and/or antioxidant sources, most especiallydietary antioxidants, alone or, preferably, in combination with b) oneor more hydrating agents and/or c) one or more keratolytic agents. Theselect antioxidants/antioxidant sources are black walnut extract,rosemary essential oil, green tea extract, pomegranate juice extract,alma extract, licorice extract, licorice white extract, pumelo extract,citrus peel extract, poria extract, boswellia extract, and turmeric aswell as the individual antioxidant components thereof and of other plantbased extracts, especially food extracts, includinghydroxy-1,4-naphthoquinones and/or the precursors and/or derivativesthereof, especially the hydro-, di-hydro-, and trihydroxy- precursorsthereof; catechins, especially epigallocatechin gallate (EGCG),epigallocatechin (EGC), epicatechin gallate (ECG) and epicatechin(EC),isothiocyantes including 4-ethydisulfinylbutylisothiocynate;carnosol; carnosic acid; ursolic acid; rosmarinic acid; tannins;flavonoids; ellagic acid, allagetannic acid; anthocyanin; β-glucogallin,mucic acid, gallic acid, mucic acid gallates, including mucic acid1,4-lactone 5-O gallate, mucic acid 1-methyl ester 2-O-gallate and mucicacid 6-O-gallate; glycyrrhizinic acid; glycyrrhetinic acid; glabridin;liquirtin; isoliquirtin; α-pinene; 1,8 cineole; camphor; borneaol;ferulic acid; camphene; linalool; d-lirnonene; apigenin; myrcene;caryopheyllene; lanotstane-type triterpenoids such as dehyrotumilosicacid; and boswellic acids such as 11-keto-boswellic acid,acetyl-11-keto-boswellic acid. While the preferred antioxidants andtheir precursors are the naturally occurring ones, i.e., extracts ofvarious plants, seeds and fruits, e.g., in the case of black walnutextracts and their antioxidant components and precursors, extractsderived from the Juglandaceae family, synthetic antioxidants as well asthe natural and synthetic precursors and derivatives corresponding tosaid preferred antioxidants are also suitable. Most preferably, thesecompositions will include suitable hydrating/humectant and/orkeratolytic agents including, but not limited to, urea, salicylic acid,glycerin, lactate and salts thereof, especially zinc lactate. Typically,these treatment compositions, or the components thereof, will beincorporated into a cosmetically acceptable and/or a pharmaceuticallyacceptable carrier or excipient and/or as a component of a cosmeticcomposition and/or topically applied pharmaceutical composition forapplication to the afflicted skin.

The present teaching also pertains to a method of treating seborrheickeratosis which method comprises applying the aforesaid treatmentcomposition or a topical composition comprising the same to seborrheickeratoses in an amount effective to reduce the size of or eliminate theseborrheic keratoses. Application may be with or without occlusion,though it is preferably with occlusion. The treatment is applied for aperiod of up to six, more typically for a period of up to four weeks.Longer application periods may be employed; however, there is oftentimesno or little benefit by the continued extended application periods.Furthermore, even when the application is ended after four or six weeks,oftentimes the seborrheic keratoses will continue to diminish.

The compositions according to the present teaching may, and preferablydo, also comprise one or more cosmetic or pharmaceutical actives thatsupplement or facilitate the treatment of the seborrheic keratosisand/or counteract or mitigate any skin damage, discoloration, discomfortand/or inflammation of the skin caused by the treatment composition orits components. Especially preferred are hydrating agents, humectants,and exfoliants, keratolytic agents, and desquamation agents (the lattercollectively referred to as keratolytic agents) including thosementioned above.

DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B are photographs of the progression of diminution of theseborrheic keratoses in Case Study 1.

FIGS. 2A, 2B and 2C are photographs of the progression, of diminution ofthe seborrheic keratoses in Case Study 2.

FIGS. 3A and 3B are photographs of the progression of diminution of theseborrheic keratoses in Case Study 3.

FIGS. 4A and 4B are photographs of the progression of diminution of theseborrheic keratoses in Case Study 4.

FIGS. 5A, 5B, 5C and 5D are photographs of the progression of diminutionof the seborrheic keratoses in Case Study 5.

FIGS. 6A, 6B, 6C and 6D are photographs of the progression of diminutionof the seborrheic keratoses in Case Study 6.

FIGS. 7A, 7B, 7C, 7D and 7E are photographs of the progression ofdiminution of the seborrheic keratoses in Case Study 7.

FIGS. 8A, 8B, 8C and 8D are photographs of the progression of diminutionof the seborrheic keratoses in Case Study 8.

DETAIL DESCRIPTION OF THE INVENTION

As used in the present specification and claims, the following termsshall have the meanings as presented:

“Pharmaceutically acceptable” means that the subject of this descriptorhas been approved or is otherwise approvable by a regulatory agency of agovernment or governmental authority or is listed in the U.S.Pharmacopoeia or other generally recognized pharmacopoeia for use inanimals, and more particularly in humans.

“Cosmetically acceptable” means that the subject of this descriptor hasbeen accepted or otherwise acceptable for use in the cosmetic and skincare industry for skin contact.

“Treating” or “treatment” in relation to seborrheic keratosis refers tothe diminution in the size, appearance, coloration and/or excision,exfoliation or sloughing off of the seborrheic keratosis.

“Optional” or “optionally” means that the subsequently describedsubject, event or circumstance may or may not occur, and that thedescription includes instances where the event occurs and instanceswhere it does not and/or when the subject is present and when it is notpresent.

“Effective amount” refers to the amount of a compound or compositionsthat, when administered to seborrheic keratosis, is sufficient to effecta visible diminution in the size, appearance, and/or coloration and/orthe ablation, exfoliation or sloughing off of the seborrheic keratosis.The “effective amount” can vary depending on, for example, the specificantioxidant or antioxidant combination or source thereof (i.e., extract)employed and the purity of the foregoing as well as the overallformulation of the composition to be applied. An appropriate amount inany given instance can be ascertained by those skilled in the art and/oris capable of determination by simple, routine experimentation.

“Natural” when used in relation to a compound or material refers to suchcompound or material that is partially or wholly isolated from orpurified from a biological material. The partial or complete isolationor purification can be by any of a number of physical, chemical and/orother procedures known in the art. For purposes of this specification, asalt of the partially or wholly purified isolated compound or materialis also to be considered a natural compound or material.

“Synthetic” when used in relation to a compound or material refers tosuch compound or material that is created or derived through chemicalsynthesis, chemical reaction, chemical derivation (as opposed toextraction from a biological material), biochemical conversion or thelike, or combinations of the foregoing. A synthetic compound can bestructurally the same as, or the chemical equivalent of, a naturalcompound and/or can be derived from a natural compound by syntheticprocesses.

“Extract” when used in relation to a biological organism, e,g., membersof the Juglandaceae family, refers to both physical elements of theorganism itself, such as ground, minced or chopped leaves, bark, roots,root bark, hulls (especially green hulls), seeds, seed pods, nuts,fruits, fruit peels (especially dried fruit peels), and the like, aswell as extracts, as thought of traditionally, where the foregoing issubject to chemical processing whereby the desired chemical(s) isremoved from the physical elements of the organism and recovered. Mostpreferably, the extracts used in accordance with the teaching of thepresent disclosure are of the latter type.

“Derivative” when used in reference to an antioxidant means bothtraditional derivatives which arise from a reaction or conversion fromthe given antioxidant as well as the precursors thereof which give riseto the select antioxidant as a result of a reaction, oxidation orconversion of the given precursor therefor. For example, in the case of1,4-naphthoquinones, derivatives thereof include that arise from areaction or conversion from the given 4-naphthoquione as well as theprecursors thereof which give rise to the select 1,4-naphthoquinone as aresult of a reaction, oxidation or conversion of the given precursor.Exemplary precursors of 1,4-naphthoquione include, for example, α- andβ- hydrojuglone, 2,3-dihydro-1,4-naphthoquinone and 1,4,5-trihydroxynaphthalene and its glycoside.

Erring on the side of caution and in an effort to avoid havingoverlooked or inadvertently omitted certain descriptive matter,particularly complementary and supplementary descriptive matter, it ishereby stated and affirmed that the technical publications as well asthe patent and patent application publications mentioned herein are allincorporated herein in their entirety by this reference. Indeed, forexample, while the current specification could present page after pageof description of suitable cosmetically acceptable and pharmaceuticallyacceptable vehicles, such would not be productive as the same are wellknown and well recognized by those skilled in the art and those thatcome into being subsequent to the filing of this application willreadily be appreciated as suitable as well. The same holds true for manyother potential constituents, both active and non-active, that can beemployed in topical compositions, especially topical skin treatments,cosmetics creams, and the like, made in accordance with the presentteachings.

According to the first aspect of the present teaching there are providedtopically applied compositions for the treatment of seborrheic keratosiswhich compositions comprises a) one or more, preferably a combinationof, select antioxidants and/or antioxidant sources, most especiallydietary antioxidants, alone or, preferably, in combination with b) oneor more hydrating and/or humectant agents and/or c) one or morekeratolytic agents. Specifically, it has been found that topicalcompositions containing the aforementioned antioxidants and/orantioxidant sources, especially those further containinghydrating/humectant agents and/or keratolytic agent, are capable ofreducing the size, appearance, coloration of the seborrheic keratosesand/or inducing or effecting the excision, exfoliation or sloughing offof the seborrheic keratosis. While other active agents known or foundeffective for treating seborrheic keratosis may be present, they are notnecessary: though they supplement and may expedite the effect of thepresently claimed, seborrheic keratosis treatment composition.

In accordance with a second aspect of the present teaching there areprovided topical compositions for treatment of seborrheic keratosiscomprising A) a seborrheic keratosis treatment composition comprising a)one or more, preferably a combination of, select antioxidants and/orantioxidant sources, most especially dietary antioxidants, alone or,preferably, in combination with b) one or more hydrating and/orhumectant agents and/or c) one or more keratolytic agents in B) acosmetically acceptable and/or a pharmaceutically acceptable carrier orexcipient and/or as a component of a cosmetic or other health and beautyaid composition and/or a topically applied pharmaceutical compositionfor application to the afflicted skin. The preferred seborrheickeratosis treatment component (A) consists essentially of a) one ormore, preferably a combination of, dietary antioxidants and/orantioxidant sources, b) one or more hydrating agents/humectants and c)one or more keratolytic agents. Preferably, especially if thecomposition is to be applied with occlusion, the topical compositioncomprises the seborrheic keratosis treatment composition as the soleactive component in a cosmetically acceptable and/or a pharmaceuticallyacceptable carrier or excipient since it is the desire of the individualapplying the same to address the seborrheic keratosis and not otherissues or skin conditions. Of course, if there is another skin maladyaffecting the same general area of the skin as the seborrheic keratosis,other pharmaceutical actives appropriate for that other malady will beincorporated into the topical composition as well. Alternatively, if thetopical composition is to be applied without occlusion, then it isoftentimes desirable to incorporate the seborrheic keratosis treatmentcomposition in a cosmetic composition which includes components designedto cover or mask the area treated, especially the visual prominence ofthe seborrheic keratoses.

Finally, according to yet another aspect of the present teaching thereis provided a method for the treatment of seborrheic keratosis whichmethod comprises applying to the seborrheic keratoses the seborrheickeratosis treatment composition, most especially a topical compositioncomprising the seborrheic keratosis treatment composition as describedabove and, in more detail, below.

The most critical component of the seborrheic keratosis treatmentcompositions of the present teaching is the antioxidant and/orantioxidant source, especially dietary antioxidants and antioxidantsources. While many dietary antioxidants and sources thereof are knownand are known to affect many organs and operations of the body,including the skin, only select dietary antioxidants have been foundsuitable or efficacious for treating seborrheic keratosis. For example,resveratrol, n-acetyl cysteine, caffeic acid and lycopene, whileeffective agents in other human biological applications, were not foundto improve the treatment of seborrheic keratosis. The selectantioxidants/antioxidant sources suitable for use in the presentteaching are Juglandaceae extracts, black walnut extract, rosemaryessential oil, green tea extract, pomegranate juice extract, almaextract, licorice extract, licorice white extract, pumelo extract,citrus peel extract, poria extract, boswellia extract, and turmeric aswell as the individual antioxidant components thereof and of other plantextracts, especially food extracts, including thehydroxy-1,4-naphthoquinones, especially the hydro-, di-hydro-, hydroxy-and trihydroxy-precursors thereof, including5-hydroxy-1,4-naphthoquinone (juglone), 1,4,5-trihydroxynaphthaleneand/or the glycosides or esters thereof, and2,3-dihydro-5-hydroxy-1,4-naphthoquinone, most preferably 5-hydroxy-1,4-naphthoquinone; catechins, especially epigallocatechin gallate(EGCG), epigallocatechin (EGC), epicatechin gallate (ECG) andepicatechin (EC),isothiocyantes including4-ethydisulfinylbutyl-isothiocyriate; carnosol; carnosic acid; ursolicacid; rosmarinic acid; tannins; flavonoids; ellagic acid, allagetannicacid; anthocyanin; β-glucogallin, mucic acid, gallic add, mucic acidgallates, including mucic acid 1,4-lactone 5-O gallate, mucic acid1-methyl ester 2-O-gallate and mucic acid 6-O-gallate; glycyrrhizinicacid; glycyrrhetinic acid; glabridin; liquirtin; isoliquirtin; α-pinene;1,8-cineole; camphor; borneaol; ferulic acid; camphene; linalool;d-limonene; apigenin; myrcene; caryopheyllene: lanotstane-typetriterpenoids such as dehyrotumilosic acid; and boswellic acids such as11-keto-boswellic acid, acetyl-11-keto-boswellic acid. While thepreferred antioxidants and their precursors are the naturally occurringones, i.e., extracts of various plants, seeds and fruits, e.g., in thecase of black walnut extracts and their antioxidant components andprecursors, extracts, derived from the Juglandaceae family, syntheticantioxidants as well as the natural and synthetic precursors andderivatives corresponding to said preferred antioxidants are alsosuitable.

For convenience, rather than go into detail into each of the selectantioxidants and antioxidant extracts, all of which are well known inthe art, for exemplary purposes attention is now given to black walnutextract and, in, particular, its key antioxidants. Specifically, one ofthe key antioxidants or groups of antioxidants suitable for use in thepractice of the present teaching are the1,4 naphthoquinones. Thoughthese are attainable synthetically, most often they are derived fromextracts of components (e.g., seed, fruit, fruit pod, bark, leaves,roots, etc.) of the Juglandaceae family, most especially extracts of theblack walnut trees. The 1,4 naphthoquinones generally have the structureI

wherein X is hydrogen, hydroxyl, methyl, methoxy, quarternary amine,ketone, a C₃ to C₇ cycloalkyl, C₂ to C₃ alkyl, 1-alkylaminoalkyl, oralkanoyl groups or a pharmaceutically acceptable salt and/or derivativesthereof. Additional ring substitution can also be present as long as itdoes not adversely affect the effectiveness of the 1,4-naphthoquinone,i.e., additionally ring substitution can have no impact on or can alter,but not abolish, the seborrheic keratosis treatment activity of the 1,4naphthoquinone. Exemplary additional ring substitutions includehalogens, such as chlorine, bromine and fluorine, and oxygenated groupssuch as phosphates, nitrates, sulphates, or other groups or substituentssuch as methoxy, carboxy, carboxylate, carboxyl-lower alkyl, hydroxy,hydroxylates, quarternary amines, glucosyl, glucosylamine, or a varietyof branched or straight chain alkyl groups, including methyl. In thisrespect, the additional ring substitution can be a useful means toincrease or decrease solubility as necessary for the final topicalformulation into which it is incorporated. As is apparent to one skilledin the art, a hydrophilic substituent should increase solubility in awater or aqueous based composition or component whereas a hydrophobicand/or lipophilic substituent should decrease solubility in a water oraqueous based composition or component and increase solubility in alipophilic or oil based composition or component, respectively.

As noted, derivatives and precursors of the compounds of structure I canalso be used. Such derivatives include those compounds of structure I inwhich one or both of the keto groups are substituted with a hydroxyl,glycoside or ester group. Additional derivatives that can be used aredisclosed in, e.g., Stich et. al. (US Patent Application Publication US2012/0322889). Preferably, the compounds according to structure I are5-hydroxy-1,4-naphthoquinone (juglone), 1,4,5-trihydroxynaphthaleneand/or the glycosides or esters thereof, and2,3-dihydro-5-hydroxy-1,4-naphthoquinone, most preferably5-hydroxy-1,4-naphthoquinone.

As noted, suitable and preferred sources of the 1,4-naphthoquinonecompounds and/or extracts containing the same are the plants and treesof the Juglandaceae family. These are well known and include the membersof the Juglans genus including Japanese walnut, common walnut, blackwalnut, Manchurian walnut, white walnut, etc., many of which areidentified in “Taschenbuch der Drogenkunde” by Heinz A. Hoppe, Walter deGruyter, Berlin, N.Y., 1981, pages 155-156; Hegnauer R., “Chemotaxonomieder Pflanzen” Volume IV, 1966. p. 281 and Hegnauer R., “Chemotaxonomieder Pflanzen” Volume VIII, 1989, p. 575. Preferred sources are JuglansRegia L. (common walnut) and Juglans Nigra L. (black walnut), mostespecially black walnut. Other members of the Juglandaceae family thatserve as sources of the extract include the members of the Carya genus,e.g., pecan and hickory, especially the members of the pecan species.The extract may comprise or be prepared from the bark, roots (especiallyroot bark), leaves, nuts, dried fruit peels, or hulls especially greenhulls. When the extract comprises the physical elements of the plant, itis typically ground or comminuted to increase surface area such that the1,4-naphthoquinone compound and/or derivative is readily released intothe carrier or composition in which the material is combined forapplication to the skin. Most preferably, the extract is a traditionalextract in which the desired 4-naphthoquinone and/or derivative isremoved or isolated from the physical material of the plant, typicallyby solvent extraction, and recovered. Such processes are described in,for example, Wixforth (U.S. Pat. No. 5,137,717) and Mitchedlidze (U.S.Pat. No. 8,206,755). The purity of the extract, at least from theperspective of the desired 1,4-naphthoquinone or derivative content isnot relevant so long as an effective amount is present when applied tothe seborrheic keratosis. Generally, though, the extracts may be used asis, i.e., as results from the extraction process, or may be furtherpurified and/or concentrated.

Again, those skilled in the art will readily appreciate the generalapplicability of the foregoing discussion with respect to the source andisolation of the 1,4-napthoquinones to the other extracts and individualantioxidants suitable for use in the practice of the present teachings,namely rosemary essential oil, green tea extract, pomegranate juiceextract, alma extract, licorice extract, licorice white extract, pumeloextract, citrus peel extract, poria extract, boswellia extract, andturmeric as well as the individual antioxidant components thereof and ofother plant extracts, especially food extracts, including the catechins,especially epigallocatechin gallate (EGCG), epigallocatechin (EGC),epicatechin gallate (ECG) and epicatechin (EC),isothiocyantes including4-ethydisulifinylbutyl-isothiocynate; carnosol; carnosic acid; ursolicacid; rosmarinic acid; tannins; flavonoids; ellagic acid, allagetannicacid: anthocyanin; β-glucogallin, mucic acid, gallic acid, mucic acidgaliates, including mucic acid 1,4-lactone 5-O gallate, mucic acid1-methyl ester 2-O-gallate and mucic acid 6-O-gallate glycyrrhizinicacid; glycyrrhetinic acid; glabridin; liquirtin; isoliquirtin; α-pinene;1,8-cineole; camphor; borneaol; ferulic acid; camphene; linalool:d-limonene; apigenin; myrcene; caryopheyllene; lanotstane-typetriterpenoids such as dehyrotumilosic acid; and boswellic acids such as11-keto-boswellic acid, acetyl-11-keto-boswellic acid.

Although effective compositions are prepared from the individualantioxidants, for example the 1,4-naphthoquinones, it is preferred thatthe compositions of the present teaching be prepared from combinationsof such individual antioxidants, most preferably from the named extractswhich typically include multiple individual antioxidants, as well ascombinations of the named extracts or of one or more of the individualantioxidants with one or more of the named extracts. Specifically, ithas been found that the combination of antioxidants, again especiallythose found within any given extract, provide enhanced effects ascompared to the individual antioxidants themselves.

Again as noted, whether individual antioxidants or antioxidant sourcesare used, it is especially preferred that combinations of each or bothbe used, especially combinations of three or more. Indeed, it has beenfound that combinations of three or more antioxidant sources provideenhanced performance as compared to lesser antioxidants or use of theindividual antioxidants. Preferred combinations of antioxidant sourcesinclude black walnut extract, green tea extract, pomegranate juiceextract and turmeric; black walnut extract, green tea extract,pomegranate juice extract and rosemary essential oil; black walnutextract, green tea extract, pomegranate juice extract, turmeric androsemary essential oil; black walnut extract, green tea extract, amlaextract, rosemary extract and licorice extract; black walnut extract,green tea extract, amla extract and licorice; green tea extract,pomegranate juice extract and turmeric; green tea extract, pomegranatejuice extract and rosemary essential oil; and green tea extract,pomegranate juice extract, turmeric and rosemary essential oil; greentea extract, amla extract, rosemary extract and licorice extract; greentea extract, and extract and licorice.

The amount of the antioxidant(s) and/or antioxidant source(e) beincorporated into the topical composition for use in the treatment ofseborrheic keratosis is at least an effective amount. The specificamount will vary depending upon the purity thereof as well as, in part,the desired speed of efficacy and/or concerns for any detrimentaleffects associated with or arising from the select antioxidant(s) and/orantioxidant source(s), including their components and derivatives aswell as any byproducts, contaminants, and the like contained therein orarising therefrom. For example it is known that topical application ofblack walnut extract causes a skin darkening effect. Hence, it may bedesirable to employ concentrations of such extracts which do notmarkedly affect skin coloration. On the other hand, since the skin colorof the area of the skin underlying the seborrheic keratoses isoftentimes lighter than the adjacent skin, it may be desirable to useconcentrations that do provide some level of skin coloration.

Generally speaking, the amount of the individual antioxidant orderivative (whether part of an extract or not) is present in an amountof from about 0.001 to about 10%, preferably from about 0.01 to 2%, byweight based on the total weight of the topical composition. Higherconcentrations can be used but may lead to detrimental effects on theskin and, possibly, toxicity concerns. Notwithstanding the foregoing, itis to be appreciated that when an, unpurified extract is employed,especially one which contains some or all of the plant matter itself,the amount of the desired antioxidant or derivative present therein isbased on the content of the desired antioxidant or derivative itself,excluding the plant matter. For example, in the case of black walnutextract, one may incorporate 50% by weight of a an extract comprising40% by weight finely ground walnut hull in a carrier such as awater/alcohol combination into a cosmetic carrier for an extract contentof 20%; yet, the amount of 1,4-naphthoqinone or derivative isconsiderably less since the concentration of 1,4-naphthoquinone orderivative in the ground hull is typically just a few percent.

The preferred seborrheic keratosis treatment compositions according topresent teaching comprise the aforementioned anitoxidants and/orantioxidant sources (or their derivatives and/or precursors) the containone or more hydrating agents and/or one or more keratolytic agents, mostpreferably both. The make-up of these preferred seborrheic keratosistreatment compositions are typically 2 to 40%, preferably 5 to 30% mostpreferably 10 to 25% antioxidant or antioxidant sources: 30 to 90%,preferably 45 to 85% most preferably from 50 to 80% hydrating agent andfrom 0.5 to 20, preferably 1 to 15, most preferably from 2 to 10%keratolytic agent.

Preferably, though riot necessarily, a plurality of antioxidants orantioxidant sources is employed in the preparation of these seborrheickeratosis treatment compositions. Again, the amount of any oneantioxidant and/or antioxidant source depends upon the purity of theantioxidant or antioxidant source, the concentration of the antioxidantsin the antioxidant source, the relative strength of each in facilitatingthe treatment of the seborrheic keratoses, etc. In general individualantioxidants, especially those in a purer or concentrated form arepresent in an amount of 0.1 to 15%, preferably 1 to 10% whereasantioxidant sources, especially the less concentrated ones, aretypically used in amount of from 2 to 30%, preferably 4 to 25%.Generally, speaking, the hydrating agents and keratolytic agents arepresent in amounts consistent for their typical use in cosmetic and skincare applications.

Suitable hydrating agents, especially those used in the skin care andcosmetics industries, are well known and typically characterized ashumectants and/or moisturizers. Preferably the hydrating agent comprisesone or more humectants, one or more moisturizers or a combination ofboth.

Humectants and moisturizers are typically characterized as beingpolyhydric alcohols, especially polyalkylene glycols and, morepreferably, alkylene polyols and their derivatives. Exemplaryhurnectants and moisturizers include propylene glycol, dipropyleneglycol, polypropylene glycol, polyethylene glycol,2-pyrrolidone-5-carboxylate, hydroxypropyl sorbitol, hexylene glycol,butylene glycol, ethoxydiglycol, 1,3-butylene glycol, 1,2,6-hexanetriol,triethylene glycol, glycerin, sugar alcohols (such as sorbitol,glycerol, xylitol, maltitol), urea, aloe vera gel, alpha hydroxy acids(such as lactic acid) and the metal salts thereof (such as zinclactate), β-glucans such as sodium carboxymethyl β-glucan, glyceryltriacetate, polymeric polyols (such as polydextrose), glycerin,ethoxylated glycerin, propoxylated glycerin, compatible solutes, such asectoin, hydroxectoin, taurines, carnithine, acetyl carnithine andmixtures thereof, etc.

Optionally, though again preferably, the seborrheic keratosis treatmentcompositions contain a keratolytic agent, i.e., exfoliants, keratolyticagents, and/or desquamation agents. As with the hydrating agents,keratolytic agents are well known in the skin care and cosmeticindustry. Preferred keratolytic agents are the dermatological acids,including, but are not limited to, fatty acids, benzylic acids, hydroxyacids, keto acids, sugar acids and retinoids as well as analogs andcombinations of the foregoing.

Suitable dermatological fatty acids include those fatty acids having oneor more carboxyl (COOH) groups, particularly at least one carboxyl endgroup, and from 6 to 20 carbon atoms, inclusive of those of the carboxylgroup. Suitable analogs include the lower alkyl esters thereof, e.g.,the C₁ to C₄ alkyl esters, especially the ethyl esters. Exemplarydermatological fatty acids include azelaic acid, lauric acid, myristicacid, stearic acid, palmitic acid, arachidic acid, behenic acid,linoleic acid, alpha-linoleic acid, oleic acid, arachidonic acid, andthe like.

Benzylic acids are generally of the formula (I):

wherein R₁, R₂, R₃, R₄ and R₅ are each independently selected from thegroup consisting of H, OH, F, I Br, Cl, SH, NH₂, C₁₋₄ alkyl, C₁₋₄alkoxyl, OR, COR, COOR, CONR₂ and SO₃R wherein R is independentlyselected from H, C₁₋₄ alkyl and C₁₋₄ alkoxyl groups. Exemplary compoundsof this formula include benzoic acid, 3-hydroxy benzoic acid, andsalicylic acid.

Retinoids are compounds that are chemically related to vitamin A andgenerally include a cyclic group having a polyene side chain (typicallyhaving conjugated double bonds) with a polar end group. Suitableretinoids include first generation retinoids such as retinol, tretinoin,and isotretinoin; second generation retinoids such as etretinate andacitretin; and third generation retinoids such as tazarotene, adapaleneand bexarotene. Especially useful retinoids include adapalene,tretinoin, isotretinoin, and tazarotene.

Sugar acids include the glyceric acids (acids based on glycerol),ascorbic acid, and glucuronic acid.

Hydroxy acids are aliphatic, cyclic, heterocyclic and aromaticcarboxylic acids having at least one hydroxyl group in addition to thecarboxylic group or groups. The most common hydroxy acids are the alpha-and beta- hydroxy acids, i.e., those hydroxy acids where the hydroxylgroup is on the carbon atom next to or once removed from, respectively,the carboxyl carbon atom. Hydroxy acids may have a single hydroxyl groupor a plurality of the same as well as a single carboxyl group or aplurality thereof. Furthermore, they may be used alone or in combinationwith other hydroxy acids or derivatives thereof, especially the simpleesters (especially the C₁₋₄ alkyl esters) and ammonium salts thereof.Exemplary hydroxy acids include, but are not limited to: glycolic acid,lactic acid, citric acid, malic acid, tartaric acid, mandelic acid,gluconic acid, glycolic acid+ammonium glycolate, alpha-hydroxyethanoicacid+ammonium alpha-hydroxyethanoate, alpha-hydroxyoctanoic acid,alpha-hydroxycaprylic acid, hydroxycaprylic acid, mixed fruit acid,triple fruit acid, tri-alpha hydroxy fruit acids, sugar cane extract,alpha hydroxy and botanical complex, L-alpha hydroxy acid, salicylicacid, beta hydroxybutanoic acid, tropic acid, and trethocanic acid.

Other dermatological acids include, for example, trichloroacetic acid,the keto acids such as pyruvic acid and ethyl pyruvate, and the like.

Although the seborrheic keratosis treatment compositions and/or thepreferred keratosis treatment compositions could be applied to the skindirectly, they are most preferably applied as a component/as componentsof a topical composition comprising the seborrheic keratosis treatmentcomposition in a cosmetically acceptable and/or a pharmaceuticallyacceptable carrier or excipient and/or as a component of a cosmeticcomposition and/or topically applied pharmaceutical composition.Preferably, the carriers or excipients are suitable for application,especially long term and repeated application, preferably underocclusion such as obtained with Nexcare or similar water-resistancebandage, to the skin without manifesting sensitization or irritation orinflammation. Generally speaking, the carrier or excipient will comprisefrom about 0.1 to about 99.999% by weight of the topical compositions,though when the preferred seborrheic keratosis treatment compositionsare employed the carrier or excipient will comprise from about 0.1 toabout 80%, preferably from about 20 to 70% by weight of the topicalcompositions. Suitable carriers and excipients include any of the knowntopical excipients and like agents necessary for achieving theparticular form of the skin care composition desired. Exemplaryexcipients include, e.g., mineral oils and emulsifying agents as well aswater, alcohol, or water/alcohol combinations, or other solvent(s) orsolvent systems in which the aforementioned actives may be, e.g.,soluble, dispersed, emulsified, etc. Preferably, though, the skin carecompositions will include excipients and the like that create asubstantially stable, homogenous composition and/or provide body,improved partition coefficient, and viscosity to the composition so thatthe actives do not merely run off the skin once applied.

Generally speaking, any known carrier or base composition employed intraditional skin care/treatment compositions may be used in the practiceof the present invention. Suitable carriers and carrier compositions aredescribed at length in, for example, Gonzalez et. al.—U.S. Pat. No.7,186,404; Aust et. al.—U.S. Pat. No. 7,175,834; Roseaver et. al.—U.S.Pat. No. 7,172,754; Simoulidis et. al.—U.S. Pat. No. 7,175,835; Mongiatet. al.—U.S. Pat. No. 7,101,536: Maniscalco—U.S. Pat. No. 7,078,022;Forestier et. al. U.S. Pat. No. 5,175,340, U.S. Pat. No. 5,567,418, U.S.Pat. No. 5,538,716, and U.S. Pat. No. 5,951,968; Deflandre et. al.—U.S.Pat. No. 5,670,140; Chaudhuri—U.S. Pat. No. 6,831,191, U.S. Pat. No.6,602,515, U.S. Pat. No. 7,166,273, U.S. Pat. No. 6,936,735, and U.S.Pat. No. 6,699,463; Chaudhuri et. al.—U.S. Pat. No. 6,165,450 and U.S.Pat. No. 7,150,876; Bonda et. al. U.S. Pat. No. 6,962,692; Rodan et,al.—U.S. Pat. No. 9,144,434, Wang et, al. U.S. Pat. No.S 5,830,441 andAuspitz et. al.—US 2007/0110685 A1. Those skilled in the art willreadily recognize and appreciate what carriers may be employed in lightof the intended form and/or delivery method for the seborrheic keratosistreating compositions.

The seborrheic keratosis treatment composition as well as the topicalcompositions are manufactured by means of conventional mixing,dissolving, granulating, dragee-makino, levigating, encapsulation, andemulsifying processes. The topical compositions can be formulated in aconventional manner using one or more physiologically acceptablecarriers, diluents, excipients, or auxiliaries, which facilitateprocessing of the seborrheic keratosis treatment composition or itscomponents with one or more acceptable carriers or excipients. Thetopical compositions according to the present teaching can take the formof solutions, suspensions, emulsions, liquids, powders, creams, lotions,gels, sustained-release formulations, aerosols, sprays, or any otherform suitable for topical administration to the skin. Most preferably,the seborrheic keratosis treatment composition as well as the topicalcompositions are in the form of a lotion, cream, gel or the like whichremains at the site of application. Lower viscosity compositions, e.g,liquid, solutions, suspensions, etc. may be used where the applicationsite is to be occluded and the composition is wicked into or saturatedinto the occluding bandage or material.

Though a carrier by itself is sufficient for effecting the diminution orexfoliation of the seborrheic keratoses, it is preferable that thetopical compositions of the present teaching include various othercomponents typically associated with skin care/treatment productsincluding, especially, cosmetic and/or pharmaceutical actives thatsupplement or facilitate the treatment of the seborrheic keratosisand/or counteract or mitigate any skin damage, discoloration, discomfortand/or inflammation of the skin treated with the seborrheic keratosistreatment composition. Such co-constituents include, but are not limitedto antioxidants, sunscreens, skin lightening actives, vitamins,anti-inflammatory agents, compatible solutes, emollients and the like,and mixtures thereof, in their conventional amounts. Exemplary agentsand additive materials are described briefly below as well as in theaforementioned patents, especially Maniscalco—U.S. Pat. No. 7,078,022.Each of these will be present in their conventional amount, though, asnoted above and in the following examples, certain of these additiveswill manifest a synergy with the isohexides of the present applicationwhereby the same performance may be realized with lesser amounts. In anyevent, such ingredients will typically be present in an amount of 1 to30 wt %, preferably 2 to 20 wt %; though again, more active or highlyactive ingredients, like the sunscreen actives, antioxidants,anti-inflammatory agents, and the like are effective at levels as low as0.01 wt %, preferably 0.1 wt %.

Suitable antioxidants include, but are not limited to, water-solubleantioxidants such as sulfhydryl compounds and their derivatives (e.g.,sodium metabisulfite and N-acetyl-cysteine), lipoic acid, alpha lipoicacid and dihydrolipoic acid, resveratrol, lactoferrin, and ascorbic acidand ascorbic acid derivatives (e,g., ascorbyl palmitate and ascorbylpolypeptide). Oil-soluble antioxidants suitable for use in thecompositions of this invention include, but are not limited to,butylated hydroxytoluene, retinoids (e.g., retinol and retinylpalmitate), tocopherols (e.g., tocopherol acetate), tocotrienols,alkylresorcinols, meroterpenes, curcurmin and its derivatives andubiquinone. Natural extracts containing antioxidants suitable for use inthe compositions of this invention, include, but not limited to,extracts containing flavonoids and isoflavonoids and their derivatives(e.g., genistein and diadzein), extracts containing resveratrol and thelike. Examples of such natural extracts include grape seed, green tea,pine bark, Phyllanthus emblica, Tenminatia chebula Terminalia balerica,and Phyllanthus amarus. Other examples of antioxidants may be found onpages 1612-13 of the ICI Handbook as well as in Ghosal—U.S. Pat. No.6,124,268.

Since the skin being exposed following removal of the seborrheickeratoses is typically lighter than the adjacent skin, it is beneficialto include one or more sunscreen actives into the topical compositions.Both organic and inorganic sunscreen active can be used. Similarly, onecan use sunscreen actives or combinations of sunscreen actives toprotect against UV-A, UV-B or both. The amount of the sunscreen activeto be incorporated into the sunscreen formulations is that which isconventional in the art. Typically, the amount is dependent upon, amongother factors, the delivery means, e.g., is it applied as a spray orlotion; the stability of the active; the efficacy of the selectedsunscreen active itself; and the application rate, as well as theparticular SPF desired. From the commercial perspective, another factorinfluencing the level of such sunscreen actives in the sunscreenformulations is the regulatory limitations on their use. In the UnitedStates, for example, strict controls are placed upon the maximum levelat which approved sunscreen actives may be present. Similarregulatory/governmental controls may also dictate which sunscreenactives may be used and at what amount in other countries as well.

Suitable organic sunscreen actives include, for example, avobenzone,butyl methoxydibenzoylmethane, cinoxate, benzophenone-8, dioxybenzone,homosalate, octylsalate, menthyl anthranilate, octocrylene, ethyhexyl,methoxycinnamate, octyl methoxycinnamate, octyl salicylate, oxybenzone,padimate O, ethylhexyl salicylate, benzophenone-3, phenylbenzimidazolesulfonic acid, sulfisobezone, trolamine salicylate, 4-methylbenzylidenecamphor, bisoctrizole, bemotrizinol, ecamsule, drometrizole trisiloxane,disodium phenyl dibenzimidazole tetrasulfonate, diethylaminehydroxybenzoyl hexyl bezoate, octyl triazone, hexyl benzoate,benzophenone-4, ethyhexyl triazone, diethylhexyl butamido triazone,bisimidazylate, polysilicone-15, etc. Suitable inorganic sunscreensinclude, but are not limited to, microfine surface treated titaniumdioxide and microfine untreated and surface treated zinc oxide. Mostpreferably, if a sunscreen active is present, the topical compositionswill comprise a combination of such sunscreen actives.

The skin care compositions of the present invention can also include oneor more vitamins and/or their derivatives. Vitamins and vitaminderivatives include, for example, vitamin A, vitamin A propionate,vitamin A palmitate, vitamin A acetate, retinol, vitamin B, thiaminechloride hydrochloride (vitamin B.sub.1), riboflavin (vitamin B.sub.2),nicotinamide, vitamin C and derivatives (for example ascorbyl palmitate,magnesium ascorbyl phosphate, ascorbyl acetate), vitamin D,ergocalciferol (vitamin D.sub,2), vitamin E, DL-.alpha.-tocopherol,tocopherol E acetate, tocopherol hydrogensuccinate, vitamin K.sub.1,esculin (vitamin P active ingredient), thiamine (vitamin B₁), nicotinicacid (niacin), pyridoxine, pyridoxal, pyridoxamine, (vitamin B₆),pantothenic acid, biotin, folic acid and cobalamine (vitamin B₁₂).Preferred vitamins are, for example, vitamin A palmitate, vitamin C andderivatives thereof, DL-α-tocopherol tocopherol E acetate, nicotinicacid, pantothenic acid and biotin. Vitamin E, which is often added tocosmetic and personal care products is also preferably stabilized by thecompounds according to the invention. Additional preferred vitamins areVitamin C and K and derivatives thereof.

The topical compositions may also include one or more amino acids andtheir derivatives. Amino acids and their derivatives include, forexample, essential and non-essential amino acids and their derivatives.Eight amino acids are generally regarded as essential for humans:phenylalanine, valine, threonine, tryptophan, isoleucine, methionine,leucine, and lysine. Additionally, cysteine (or sulphur-containing aminoacids), tyrosine (or aromatic amino acids), histidine and arginine arerequired by infants and growing children. Essential amino acids are socalled not because they are more important to life than the others, butbecause the body does not synthesize them, making it essential toinclude them in one's diet in order to obtain them. In addition, theamino acids arginine, cysteine, glycine, glutamine, histidine, proline,serine and tyrosine are considered conditionally essential, meaning theyare not normally required in the diet, but must be supplied exogenouslyto specific populations that do not synthesize it in adequate amounts.Amino acid derivatives may be simple esters or amides or complexpeptides.

Suitable emollients that can be and preferably are incorporated into thetopical compositions include those agents known for softening the skinwhich may be selected from hydrocarbons, fatty acids, fatty alcohols andesters. Petrolatum is a common hydrocarbon type of emollientconditioning agent. Other hydrocarbons that may be employed includealkyl benzoate, mineral oil, polyolefins such as polydecene, andparaffins, such, as isohexadecane. Fatty acids and alcohols typicallyhave from about 10 to 30 carbon atoms. Illustrative are myristic,isostearic, hydroxystearic, oleic, linoleic, ricinoleic, behenic anderuicic acids and alcohols. Oily ester emollients may be those selectedfrom one or more of the following, triglyceride esters, acetoglycerideesters, ethoxylated glycerides, alkyl esters of fatty acids, etheresters, polyhydric alcohol esters and wax esters. Additional emollientsor hydrophobic agents include C₁₂ to C₁₅ alkyl benzoate, dioctyladipate,octyl stearate, octyldodecanol, hexyl laurate, octyldodecylneopentanoate, cyclomethicone, dicapryl ether, dimethicone, phenyltrimethicone, isopropyl myristate, capriylic/capric triglycerides,propylene glycol dicaprylate/dicaprate and decyl oleate.

Suitable anti-inflammatory ingredients include, but are not limited to,bisabolol, curcurmin and its derivatives, retinoids, flavonoids,meroterpenes (such as Bakuchiol or its derivatives) and otherpolyphenolics etc. These and other anti-inflammatory agents, as well asadditional anti-oxidants and the like, are disclosed in Gupta et. al.(US 2005/0048008A1).

The topical compositions of the present teaching can also include one ormore skin penetrants. These are additives that, when applied to theskin, have a direct effect on the permeability of the skin barrier:increasing the speed with which and/or the amount by which certain othercompounds, especially those making up the seborrheic keratosis treatmentcomposition, especially the antioxidants and/or antioxidant sources, areable to penetrate into the seborrheic keratoses. Exemplary organicpenetration enhancers include dimethyl sulfoxide; dimethyl isosorbide,dimethyl isomannide, diethyl isoidide, diethyl isosorbide, diethylisomannide, isopropyl isosorbide, isopropyl isomannide, isopropylisoidide, isopropyl myristate; decyl, undecyl or dodecyl alcohol;propylene glycol: polyethylene glycol; C₉₋₁₁, C₁₂₋₁₃ or C₁₂₋₁₅ fattyalcohols; azone; alkyl pyrrolidones; lecithin; etc. Surfactants can alsobe used as penetration enhancers. When skin penetrants are employed itis important to endeavor to limit the application of the topicalcompositions to the seborrheic keratoses themselves and avoid otherareas of the skin.

Other optional adjunct ingredients for the topical compositions of thepresent invention include preservatives, waterproofing agents,fragrances, anti-foam agents, plant extracts (Aloe vera, witch hazel,cucumber, etc), opacifiers, astingents, stabilizers, skin conditioningagents, colorants, and the like, each in amounts effective to accomplishtheir respective functions.

As evident from the foregoing, there is considerable overlap withrespect to the performance or purpose thereof among the variouscomponents of the seborrheic keratosis treatment composition and theadditives and optional ingredients that may be, and preferably are,employed in the compositions and methods of the present teaching. Forexample, urea is known to act as both a hydrating agent as well as akeratolytic agent. Similarly, there are many of the additive ingredientswhich have multiple performance capabilities.

As noted above, the present teaching also applies to a method oftreating seborrheic keratosis by applying to the seborrheic keratosesthe seborrheic keratosis treatment composition, most preferably atopical composition comprising the seborrheic keratosis treatmentcomposition, with or without occlusion. The amount of the seborrheickeratosis treatment composition that is to be applied to the skindepends upon the amount of concentration and selection of ingredients ofthe seborrheic keratosis treatment composition as well as the form ofthe seborrheic keratosis treatment composition and its mode ofapplication: typically it is an amount sufficient to wet and leave athin film on the surface of the treated skin. Most especially, theseborrheic keratosis treatment composition is applied as a component ofa topical composition, at least one having a carrier or solvent orexcipient to aid in the application of the seborrheic keratosistreatment composition. Again, the amount to be applied likewise dependsupon the amount of the sebonrheic keratosis treatment composition in thetopical composition as well as form of the topical composition. Forexample, a spray formulation may be applied so as to provide a light,even coat on the skin. Lotions, creams, gels and the like are typicallyapplied at a rate of about 0.1 to about 10 mg/cm², preferably from about1 to about 3 mg/cm², to the skin. This rate generally provides a thineven coating on the surface of the seborrheic keratoses. Regardless ofthe method of application, the key is to ensure the application of aneffective amount of the antioxidant or antioxidant source or theseborrheic keratosis treatment composition.

The seborrheic keratosis treatment composition or topical compositionsaccording to the present teaching are applied to the skin for so long anecessary to achieve the desired diminution of the seborrheic keratosesor, preferably, the complete removal thereof. Generally speaking, theyare to be applied to the skin once, typically not more often than once,a day, with the preferred time of application following showering,bathing, swimming or any other activity which tends to result in theremoval or wearing away of the previously applied composition. Ofcourse, a second or more application may be necessary where suchactivity, i.e., showering, swimming, bathing, etc., follows the initialapplication on any given day. On the other hand, daily use is notrequired, especially if the individual or the treated area is notsubject to conditions that cause the loss of the treatment. This may,however, lessen the efficacy or require longer application periods.However, if the treatment method calls for occlusion of the treatedkeratoses, it is only necessary to retreat periodically, perhaps everytwo to seven days, or as frequently as it becomes necessary to changethe bandage or dressing. Generally speaking, it is not necessary toapply the seborrheic keratosis treatment composition or topicalcomposition for more than six weeks, preferably no more than four weeks.Although the compositions could be applied for longer periods, suchlonger application is not found to improve the results. This isespecially significant since alternative compositions, including thosebased on urea and lactic acid, are said to require several months ofapplication to manifest the same results as seen with the presentcomposition.

On the other hand, it is not always necessary to apply the compositionsfor the full four or six week period as it is also found that thebenefits of the treatment continue even after application is terminated.As shown in the examples below, the seborrheic keratoses continue todiminish in size and/or appearance in the days and weeks followingcessation of the application of the present compositions. Although notintended to be bound by theory, it is believed that the seborrheictreatment compositions initiated actions and/or effected degradation ofthe seborrheic keratoses which continued and/or whose effect was notfully manifested until after treatment had stopped.

EXAMPLES

Having described he invention in general terms, attention is now turnedto the following pilot and case studies which demonstrate the efficacyof the present teachings. In each of the pilot studies and case studies1 thru 4 a liquid herbal extract of black walnut green hulls of 1:1.75wt.:vol, green hull:water-alcohol mixture (approx. 570 mg green hulls to1 ml of solvent), hereinafter “BWE” for simplicity, was employed (GaiaHerbs, Inc., Brevard, N.C.). In each of case studies 5 thru 8 a topicalcomposition in the form of a cream containing, as the antioxidantcomponent, 5% green tea extract, 5% turmeric, 0.625% pomegranate extractand 0.625% rosemary essential oil; as the humectant, 12.5% urea (whichalso acts as a keratolytic agent), 10% glycerin, and 8.75% zinc lactate;and, as the keratolytic agent, 2.5% salicylic acid, was applied toseborrheic keratoses. The quantity applied was a pea-sized amount whichgenerally provided a thin film of 3-4 mm over the surface of theseborrheic keratoses being treated. In all the case studies the treatedarea was occluded using a 3M Nexcare waterproof bandage (3M, St. PaulMinn.) following application of the treatment composition. The bandagewas changed at typical internals of 3-9 days with a reapplication of thetreatment composition. The patients were instructed to shower andexercise as normal but not scrub the area treated. At the time thebandage was removed an emery board is used to remove keratin slough andthe old topical composition. Following removal, another quantity of thetopical composition was applied and, again, the treated area occluded.

Pilot Study 1

A composition comprising BWE in a carrier was applied to SKs on a numberof individuals. It was found that the treatment reduced the size ofand/or resulted in the loss of the SKs.

Pilot Study 2

A composition comprising 20% BWE, 25% propylene glycol and 55% Aquaphor(Beiersdorf AG, Hamburg, Germany) was applied to the SKs of threepatients. The SKs were found to have cleared from the skin aftermultiple days of application.

Case Study 1

An 80-year-old female presented with a tender hyperkeratotic area on thenipple (FIG. 1A). A cream containing 7% zinc lactate and 10% urea wasapplied daily for 5 days without occlusion. No change in the keratosiswas noted. Thereafter, a cream containing 20% BWE, 8% glycerin, 7% zinclactate, 4% green tea extract, 4% turmeric, 0.5% pomegranate extract,and 0.5% rosemary was applied under occlusion for 7 days. Followingremoval of the bandage the central hyperkeratosis was found to beloosely attached and was extracted painlessly with a forceps, leavingthe nipple free of hyperkeratosis (FIG. 1B). Telephone follow-up at 8months confirmed that the lesion had not recurred.

Case Study 2

A 69-year-old male presented with an asymptomatic seborrheic keratosison the lateral calf area (FIG. 2A). Following light debridement of theSK to remove loose cells with a pumice stone a thin coating of a creamcontaining 20% BWE, 10% urea, 8% glycerin, 7% zinc lactate, 4% green teaextract, 4% turmeric, 2% salicylic acid, 0.5% pomegranate extract, and0.5% rosemary was applied to the SK and the treated area occluded. After8 days the bandage was remove and the edge of an emery board used gentlypry the dried cream and cells from the treated area. The SK was removed,though some capillary bleeding was noted (FIG. 2B). The lesion had notrecurred 20 months later (FIG. 2C).

Case Study 3

A 61-year-old female had a seborrheic keratosis on the extensor forearm(FIG. 3A). Debridement with a pumice stone was followed by applicationof the same formulation as in Case Study 2 and occlusion.

After one week the bandage removed and the dried cream and dead skincells debrided with the edge of an emery board and the cream reappliedand the occlusive bandage replaced. After another week the bandage wasremoved and the dried cream and dead skin cells debrided. The SK wasmarkedly reduced in size as seen in FIGS. 3B.

Case Study 4

A 49-year-old female had two seborrheic keratoses on the medial thigh(FIG. 4A). The composition of Case Study 2 was applied and the treatedarea occluded. Application of the mixture and removal of the keratinslough at dressing changes with an emery board resulted in thedisappearance or near disappearance of one SK and the marked reductionin size prominence and color of the other by day 24 (FIG. 4B).

Case Study 5

A 64-year-old female presented with a SK on the left lateral thigh (FIG.5A. Occlusion with the topical composition resulted in decreasedthickness by Day 8 (FIG. 5B). Removal of keratin debris followed by 6days more of occlusion with the topical composition led to furtherimprovement by Day 14 FIG. 5C). Another debridement resulted in furtherimprovement (FIG. 5D),

Case Study 6

An 81-year-old female presented with an irritated SK on the lateralabdomen (FIG. 6A). Occlusion with the topical composition followed bykeratin debris removal on Day 8 resulted in decreased thickness (FIG.6B). Another 6 days of occlusion with the topical composition followedby keratin debris removal (Day 14) led to further improvement (FIG. 6C).Note superficial ulceration at right after keratin debris removal. Theulcer was healed after three days (Day 17, FIG. 6D). This area of thehealed ulcer shows no residual SK; to the left, superficial SK remains.

Case Study 7

A 65-year-old female presented with a SK on the right calf (FIG. 7A).Occlusion with the topical composition resulted in decreased thicknessby Day 8 (FIG. 7B). Removal of keratin debris followed by 7 days more ofocclusion with the topical composition led to a small eschar by Day 15(FIG. 7C). The lesion was allowed to heal, with no further treatmentwith the topical composition and no occlusion. Healing with erythema anda thin eschar is apparent by Day 22 (FIG. 7D). The SK was not apparenton Day 63 (FIG. 7E).

Case Study 8

The same 65-year-old female presented with a SK superior to the rightpopliteal area (FIG. 8A). Occlusion with the topical compositionresulted in decreased thickness by Day 8 (FIG. 8B). Removal of keratindebris was followed by 7 days more of occlusion with the topicalcomposition and debridement on Day 15 (FIG. 8C). The lesion was allowedto heal, with no further treatment with the topical composition and noocclusion. The SK was not apparent on Day 63 (FIG. 8D).

Exemplary Formulations

A number of formulary and performance observations were made in thevarious aforementioned pilot and case studies as well as additionalvariants thereof not reported here. For example, the addition of variousnatural antioxidants and combinations thereof, especially, green teaextract, turmeric, pomegranate extract, and rosemary were found toprovide an enhanced, if not synergistic performance with the BWE. On theother hand, no visible improvement was seen with the addition of certaingeneral antioxidants, namely, resveratrol, N-acetyl cysteine, caffeicacid and lycopene. Additionally, the addition of keratolytic agents andemollients appeared to help keep the composition from drying andimproved the penetration of the composition into the SK. Similarly, itwas found that a number of ingredients including urea, zinc lactate,salicylic acid and glycerin improved hydration as well as penetrationinto the SKs. Altogether, the addition of these additional ingredientsas opposed to the BWE alone resulted in SKs that were softer at dressingchange (2-7 days), enabling the moistened keratotic debris to be liftedfrom the skin with the edge of an emery board.

Four topical seborrheic keratosis treatment compositions were preparedaccording to the formulations presented in Table 1. Formulations A and Cused deionized water whereas Formulations B and D used buffered waterwhich was prepared by adding a 1.0% citric acid solution to water to QSpH 6.8. Otherwise these formulations were prepared by combining theingredients of Phase 1 and heating to 70° C. A premix of Phase 2 wasthen added to the heated Phase 1 while mixing. Meanwhile the ingredientsof Phase 3 were combined and heated to 70° C. and then added to thecombined Phases 1 and 2 with mixing. Following the combination of Phase1, 2 and 3, the mixture was homogenized until uniform after which thecombination was allowed to cool to 45° C. At that point, a pre-mix ofthe ingredients of Phase 4 were added to the cooled mixture and the samefurther cooled to 30° C.

Without further elaboration, it is believed that one skilled in the art,using the preceding description, can utilize the present invention toits fullest extent. Furthermore, while the present invention has beendescribed with respect to aforementioned specific embodiments andexamples, it should be appreciated that other embodiments, changes andmodifications utilizing the concept of the present invention arepossible, and within the skill of one in the art, without departing fromthe spirit and scope of the invention. The preceding preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

TABLE 1 Ingredient/ Formulation Commercial Name A B C D Phase 1 Ultrez30 1.00 1.0 1.00 0.5 Water 49.50 42.00 41.40 28.6 Euxyl Pe9010 0.50 0.500.50 0.5 Glycerin 10.00 10.00 10.00 8.0 AA26/Vitamin C 2.00 Black WalnutExtract 15.0 2 Rosemary extract/ 2.00 2.00 2.00 2.0 Rosemary CG, SabinsaCorporation Amla extract/Saberry 2.00 2.00 2.00 2.0 antioxidant, SabinsaCorporation Green Tea extract/ 2.00 2.00 2.00 2.0 Sabinsa CorporationLicorice extract/licorice 2.00 2.00 2.00 2.0 CG, Sabinsa Corporation orViaPure Licorize, Actives International Ellagic acid 2.00 2.00 2.0Co-Q10 3.00 2.00 2.0 Ferulic acid/McKiney 0.50 0.5 Resources Poriaextract/ViaPure 0.50 0.5 poria, Actives International Citrus extract/0.10 0.1 Citrus Sp/ViaPure Citrus, Actives International Boswelliaextract/ViaPure 0.20 0.2 Boswellia, Actives International Beta-glucan/0.20 0.2 McKinley Resources Phase 3 Mantanov 82 4.00 4.00 4.00 4.00Glyceral stearate 3.00 3.00 3.00 3.00 Cetyl alcohol 2.00 2.00 2.00 2.00Salicylic acid 2.00 2.00 2.00 2.00 Curcumonoids 2.00 2.00 2.00 2.00Isopropyl myristate 3.00 3.00 3.00 3.00 Phase 4 Urea 10.00 10.00 10.0010.00 Zinc lactate 5.00 5.00 5.00 5.0 Vitamin E acetate 0.50 0.50 0.50Vitamn C stabilized 2.00 2.00 Total 100.00 100.00 100.00 100.00

I claim:
 1. A seborrheic keratosis treatment composition comprising a)one or more, select antioxidants and/or antioxidant sources, b) one ormore hydrating agents and c) one or more keratolytic agents wherein theselect antioxidants and antioxidant sources are selected fromJuglandaceae extracts, black walnut extract, rosemary essential oil,green tea extract, pomegranate juice extract, alma extract, licoriceextract, licorice white extract, pumelo extract, citrus peel extract,poria extract, boswellia extract, turmeric, hydroxy-1,4-naphthoduinones,catechins, isothiocyantes, carnosol, carnosic acid, ursolic acid,rosmarinic acid, tannins, flavonoids, ellagic acid, allagetannic acid,anthocyartin, β-glurogallin, mucic acid, gallic acid, mucic acidgallates, glycyrrhizinic acid, glycyrrhetinic acid, glabridin,liquirtin, isoliquirtin, α-pinene, 1,8-cineole, camphor, borneaol,ferulic acid, camphene, linalool, d-limonene, apigenin, myrcene,caryopheyllene, lanotstane-type triterpenoids, and boswellic acids. 2.The composition of claim 1 wherein the antioxidants and antioxidantsources are selected from Juglandaceae extracts, black walnut extract,rosemary essential oil, green tea extract, pomegranate juice extract,alma extract, licorice extract, licorice white extract, pumelo extract,citrus peel extract, poria extract, boswellia extract, turmeric,5-hydroxy-1,4-naphthoquinone (juglone), 1,4,5-trihydroxynaphthalene,2,3-dihydro-5-hydroxy-1,4-naphthoquinone, epigallocatechin gallate(EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), epicatechin(EC), 4-ethydisulfinyibutyl-isothiocynate, carnosol, carnosis acid,ursolic acid, rosmarinic acid, tannin, ellagic acid, allagetannic acid,anthocyanin, β-glucogallin, mucic acid, gallic acid, mucic acid gallate,mucic acid 1,4-lactone 5-O gallate, mucic acid 1-methyl ester2-O-gallate, mucic acid 6-O-gallate, glycyrrhizinic acid, glycyrrhetinicacid, glabridin, liquirtin, isoliquirtin, α-pinene, 1,8-cineole,camphor, borneaol, ferulic acid, camphene, linalool, d-limonene,apigenin, myrcene, caryopheyllene, dehyrotumilosic acid,11-keto-boswellic acid and acetyl-11-keto-boswellic acid.
 3. Thecomposition of claim 1 wherein at least one antioxidant source ispresent and is selected from Juglandaceae extracts, black walnutextract, rosemary essential oil, green tea extract, pomegranate juiceextract, alma extract, licorice extract, licorice white extract, pumeloextract, citrus peel extract, poria extract, boswellia extract, andturmeric.
 4. The composition of claim 3 wherein at least two antioxidantsources are present.
 5. The composition of claim 1 wherein theantioxidant source comprises at least three of the following: rosemaryessential oil, green tea extract, pomegranate juice extract, almaextract, licorice extract, licorice white extract, pumelo extract,citrus peel extract, poria extract, boswellia extract, and turmeric 6.The composition of claim 1 wherein the antioxidant source comprises thecombination of rosemary essential oil, green tea extract, alma extractand licorice extract, with or without black walnut extract.
 7. Thecomposition of claim 1 wherein a 1,4 naphthoquinone having the structureI

wherein X is hydrogen, hydroxyl, methyl, methoxy, quartemary amine,ketone, a C₃ to C₇ cycloalkyl, C₂ to C₃ alkyl, 1-alkylaminoalkyl, oralkanoyl group is present.
 8. The composition of claim 7 wherein the1.4-naphthoquinone is 5-hydroxy-1,4-naphthoquinone or a precursorthereof.
 9. The composition of claim 8 wherein the precursor is presentand is selected from α-hydrojuglone, β-hydrojuglone,2,3-dihydro-1,4-naphthoquinone and 1,4,5-trihydroxy naphthalene or itsglycoside.
 10. The composition of claim 1 wherein the one or moreantioxidants and/or antioxidant sources (a) are present in an amount offrom 2 to 40%, the one or more hydrating agents (b) are present in anamount of from 30 to 90% and the one or more keratolytic agents (c) arepresent in an amount of from 0.5 to 20% by weight based on thecombination of (a), (b) and (c).
 11. The composition of claim 1 furthercomprising 0.1 to about 80% by weight based on the total weight of thecomposition of a cosmetically acceptable or pharmaceutically acceptablecarrier or excipient.
 12. The composition of claim 11 further comprisingone or more sunscreens, skin lightening actives, vitamins,anti-inflammatory agents, or combinations of two or more of theforegoing.
 13. The composition of claim 1 present in an effective mountin a cosmetic or skin care product formulation,
 14. A method ofameliorating the manifestation of seborrheic keratosis comprisingapplying to the surface of the seborrheic keratoses a topicalcomposition comprising an effective amount of an antioxidant orantioxidant source selected from Juglandaceae extracts, black walnutextract, rosemary essential oil, green tea extract, pomegranate juiceextract, alma extract, licorice extract, licorice white extract, pumeloextract, citrus peel extract, poria extract, boswellia extract,turmeric, hydroxy-1,4-naphthoduinones, catechins, isothiocyantes,carnosol, carnosic acid, ursolic acid, rosmarinic acid, tannins,flavonoids, ellagic acid, allagetannic acid, anthocyanin, β-glucogallin,mucic acid, gallic acid, mucic acid gallates, glycyrrhizinic acid,glycyrrhetinic acid, glabridin, liquirtin, isoliquirtin, α-pinene,1,8-cineole, camphor, borneaol, ferulic acid, camphene, linalool,d-limonene, apigenin, myrcene, caryopheyllene, lanotstane-typetriterpenoids, and boswellic acids.
 15. The method of claim 14 whereinthe antioxidants and antioxidant sources are selected from Juglandaceaeextracts, black walnut extract, rosemary essential oil, green teaextract, pomegranate juice extract, alma extract, licorice extract,licorice white extract, pumelo extract, citrus peel extract, poriaextract, boswellia extract, turmeric, 5-hydroxy-1,4-naphthoquinone(juglone), 1,4,5-trihydroxynaphthalene,2,3-dihydro-5-hydroxy-1,4-naphthoquinone, epigallocatechin gallate(EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), epicatechin(EC), 4-ethydisulfinylbutyl-isothiocynate, carnosol, carnosic acid,ursolic acid, rosmarinic acid, tannin, ellagic acid, allagetannic acid,anthocyanin, β-glucogallin, mucic acid, gallic acid, mucic acid gallate,mucic acid 1,4-lactone 5-O gallate, mucic acid 1-methyl ester2-O-gallate, mucic acid 6-O-gallate, glycyrrhizinic acid, glycyrrhetinicacid, glabridin, liquirtin isoliquirtin, α-pinene, 1,8-cineole, camphor,borneaol, ferulic acid, camphene, linalool, d-limonene, apigenin,myrcene, caryopheyllene, dehyrotumilosic acid, 11-keto-boswellic acidand acetyl-11-keto-boswellic acid.
 16. The method of claim 14 wherein atleast one antioxidant source is present and is selected fromJuglandaceae extracts, black walnut extract, rosemary essential oil,green tea extract, pomegranate juice extract, alma extract, licoriceextract, licorice white extract, pumelo extract, citrus peel extract,poria extract, boswellia extract, and turmeric.
 17. The method of claim16 wherein at least two antioxidant sources are present.
 18. The methodof claim 14 wherein the antioxidant source comprises at least three ofthe following: rosemary essential oil, green tea extract, pomegranatejuice extract, alma extract, licorice extract, licorice white extract,pumelo extract, citrus peel extract, poria extract, boswellia extract,and turmeric
 19. The method of claim 14 wherein the antioxidant sourcecomprises rosemary essential oil, green tea extract, alma extract andlicorice extract, with or without black walnut extract.
 20. The methodof claim 14 wherein a 1,4 naphthoquinone having the structure I

wherein X is hydrogen, hydroxyl, methyl, methoxy, quarternary amine,ketone, a C₃ to C₇ cycloalkyl, C₂ to C₃ alkyl, 1-alkylaminoalkyl, oralkanoyl group is present.
 21. The method of claim 20 wherein the1,4-naphthoquinone is 5-hydroxy-1,4-naphthoquinone or a precursorthereof.
 22. The method of claim 21 wherein the precursor is present andis selected from α-hydroluglone, β-hydrojuglone,2,3-dihydro-1,4-naphthoquinone and 1,4,5-trihydroxy naphthalene or itsglycoside.
 23. The method of claim 14 wherein the antioxidant orantioxidant source is present in an amount of from about 0.001 to about10% based on the total weight of the composition.
 24. The method ofclaim 14 wherein the topical composition further comprises from 0.1 to99.999% by weight based on the total composition, of a cosmeticallyacceptable or pharmaceutically acceptable carrier or excipient.
 25. Themethod of claim 14 wherein the topical composition comprises from 2 to40% by weight of the one or more antioxidants and/or antioxidant sources(a) in combination with from 30 to 90%) by weight of one or morehydrating agents (b) and/or from 0.5 to 20% by weight of one or morekeratolytic agents (c) based on the total weight of the combination of(a) and (b) and/or (c) wherein the amount of the antioxidants and/orantioxidant sources comprise from 0.1 to 80% by weight based on thetotal weight of the topical composition.